From the Journals

Alzheimer’s: Biomarkers, not cognition, will now define disorder

View on the News

A logical and modern approach

The biologically defined amyloid beta–tau–neuronal damage (ATN) framework is a logical and modern approach to Alzheimer’s disease (AD) diagnosis. It is hard to argue that more data are bad. Having such data on every patient would certainly be a luxury, but, with a few notable exceptions, the context in which this will most frequently occur is within the context of clinical trials.

While having this information does provide a biological basis for diagnosis, it does not account for non-AD contributions to the patient’s symptoms, which are found in more than half of all AD patients at autopsy; these non-AD pathologies also can influence clinical trial outcomes.

Dr. Richard J. Caselli, professor of neurology at the Mayo Clinic in Scottsdale, Ariz., and associate director and clinical core director of Mayo’s Alzheimer’s Disease Center.

Dr. Richard J. Caselli

This expensive framework might unintentionally lock out research that does not employ all these biomarkers either because of cost or because of clinical series–based studies. These biomarkers generally can be obtained only if paid for by a third party – typically a drug company. Some investigators may feel coerced into participating in studies they might not otherwise be inclined to do.

It also seems a bit ironic that the only meaningful manifestation of AD is now essentially left out of the diagnostic framework or relegated to nothing more than an adjective. Yet having a head full of amyloid means little if a person does not express symptoms (and vice versa), and we know that all people do not progress in the same way.

In the future, genomic and exposomic profiles may provide an even-more-nuanced picture, but further work is needed before that becomes a clinical reality. For now, the ATN biomarker framework represents the state of the art, though not an end.

Richard J. Caselli, MD, is professor of neurology at the Mayo Clinic Arizona in Scottsdale. He is also associate director and clinical core director of the Arizona Alzheimer’s Disease Center. He has no relevant disclosures.



The biomarker profiles are:

  • A-T-(N): Normal AD biomarkers
  • A+T-(N): Alzheimer’s pathologic change; Alzheimer’s continuum
  • A+T+(N): Alzheimer’s disease; Alzheimer’s continuum
  • A+T-(N)+: Alzheimer’s with suspected non Alzheimer’s pathologic change; Alzheimer’s continuum
  • A-T+(N)-: Non-AD pathologic change
  • A-T-(N)+: Non-AD pathologic change
  • A-T+(N)+: Non-AD pathologic change

“This latter biomarker profile implies evidence of one or more neuropathologic processes other than AD and has been labeled ‘suspected non-Alzheimer’s pathophysiology, or SNAP,” according to the paper.

Cognitive staging further refines each person’s status. There are two clinical staging schemes in the framework. One is the familiar syndromal staging system of cognitively unimpaired, MCI, and dementia, which can be subdivided into mild, moderate, and severe. This can be applied to anyone with a biomarker profile.

Biomarker grouping and cognitive status interactions
“This three-category division serves as the basis for cognitive categorization in many large ongoing studies,” Dr. Jack and his colleagues wrote. “Numerous researchers feel that it has been and continues to be effective for clinical research and that abandoning it would unnecessarily disrupt ongoing studies.”


Next Article: